The overall objective of the proposed research is to study the addictive potential and neuronal substrates of action of long acting narcotic blocking agents developed as substitutes for methadone. Included for study will be methadone itself, morphine and morphine agonists, and a variety of long acting agents such as acetylmethadol, as well as its metabolites, including noracetylmethadol, methadol, and normethadol. The studies of addictive potential will be three-fold involving (1)the Saelen's mouse jumping test of opiate physical dependence capacity, (2) the Buckett modification of the Seevers and Deneau test for morphine-like addiction liability, and (3) a self-administration paradigm of behavioral dependence, designed to study those aspects of addiction liability diassociable from physical dependence. The studies of brain receptor mechanisms upon which acetylmethadol and other long acting narcotic substitutes may act to achieve narcotic blockade will also be three-fold. They will include (1) studies of the effects of narcotic and narcotic blocking agents on neurotransmitter-stimulated receptor and related adenylate and guanylate cyclic nucleotide systems, (2) studies of the binding of morphine to membrane receptors in the presence and absence of blocking agents such as acetylmethadol, and (3) studies of alterations in receptor and second messenger systems during chronic administration of narcotic and blocking agents and during withdrawal. Although the project outlined herein deals specifically with acetylmethadol and its metabolites, the approach can serve as a model for study of any compound introduced as a potential agent for narcotic substitution and control.